Hereditary Hemochromatosis DNA Mutation Analysis

Heterozygous means the individual carries one copy of a mutation on one chromosome. If the mutation is associated with a recessive disease such as hereditary hemochromatosis (HH), the individual is called a carrier. Carriers are typically unaffected, that is, they show no symptoms of the disease. However, a diagnosis of HH is made clinically, based on iron studies (see Question 5). If your patient has a clinical diagnosis of HH, he/she may carry a second HFE gene mutation not tested for in our panel. Additional mutation testing may be available for your patient at another lab. Call Quest Genomics Client Services at 866-GENE-INFO to discuss this case with a genetic counselor.

Homozygous means the individual carries two copies of the same mutation, one on each chromosome. If the mutation is associated with a recessive disease such as HH, the individual is typically affected, that is, he/she shows symptoms of the disease. However, a diagnosis of HH is made clinically, based on iron studies (see Question 5). A homozygous result supports a clinical diagnosis of HH, but not all individuals with two mutations will develop symptoms of iron overload. Some individuals with this genotype may be nonexpressing homozygotes. Nonexpressing homozygotes can be monitored for signs of iron overload.

Compound heterozygous means the individual carries one copy each of two different mutations, one on each chromosome. If the mutations are associated with a recessive disease such as HH, the individual is typically affected. However, a diagnosis of HH is made clinically, based on iron studies (see Question 5). A compound heterozygous result supports a clinical diagnosis of HH, but not all individuals with two mutations will develop symptoms of iron overload. These individuals can be monitored for signs of iron overload.

Question 2. What is the next step if my patient tests positive for one HH mutation?

It depends on the indication for the HH test:

This DNA test has not ruled out a diagnosis of HH. If your patient has findings that are clinically consistent with HH, he/she may carry a second mutation not tested for in our panel. Additional mutation testing may be available for your patient at another lab. Call Quest Genomics Client Services at 866-GENE-INFO to discuss this case with a genetic counselor.

If the only indication is a positive family history of HH, consider ordering iron studies on your patient to determine if he/she has findings that are clinically consistent with a diagnosis of hemochromatosis. Please call Quest Genomics Client Services at 866-GENE-INFO to discuss this case with a genetic counselor. Documentation of the specific HH mutations in the family will be necessary to determine the accuracy of the testing that was performed on your patient.

Question 3. My patient has a family history of HH and has a negative HH mutation result. Does this result guarantee that my patient is not a carrier of HH?

No, please call Quest Genomics Client Services at 866-GENE-INFO to discuss this case with a genetic counselor. Documentation of the specific HH mutations in the family will be necessary to determine the accuracy of the testing that was performed on your patient.

Question 4. My patient has a clinical diagnosis of hereditary hemochromatosis (HH), i.e., documented iron overload, but the HH mutation test performed was negative (or only one mutation was detected). What should I do next?

This DNA test has not ruled out a diagnosis of HH. If your patient has findings that are clinically consistent with HH, he/she may carry a second mutation not tested for in our panel or may have mutations in a different gene. Additional mutation testing may be available for your patient at another lab. You may also wish to consider evaluation for other conditions that may be associated with iron overload. Call Quest Genomics Client Services at 866-GENE-INFO to discuss this case with a genetic counselor.

While a homozygous (or compound heterozygous) result may indicate that your patient is affected, a diagnosis of HH is established clinically using iron studies (serum transferrin saturation and serum ferritin). If not already performed, the next step is to perform iron studies to determine whether your patient is clinically affected with HH. Therapeutic phlebotomy is indicated only if the iron studies are consistent with a diagnosis of HH. Note that iron studies may be normal in premenopausal women with HH, due to regular menses. See Figure 1 for a diagnostic algorithm.1

Figure 1. HFE-associated Hemochromatosis Screening Algorithm1

LFT, liver function test; TS, transferrin saturation.

Originally published in Eijkelkamp EJ, et al. Can J Gastroenterol. 2000;14:121. Used with permission.

Question 6. The result reported for my patient only mentions that he/she is heterozygous for the C282Y mutation. Was my patient also tested for the H63D mutation?

Yes. The assay tests for both the C282Y and the H63D mutations. So, if the result indicates that your patient is heterozygous for the C282Y mutation, then he/she is negative for the H63D mutation.

Question 7. The result reported for my patient only mentions that he/she is heterozygous for the H63D mutation. Was my patient also tested for the C282Y mutation?

Yes. The assay tests for both the C282Y and the H63D mutations. So, if the result indicates that your patient is heterozygous for the H63D mutation, then he/she is negative for the C282Y mutation.

This FAQ is provided for informational purposes only and is not intended as medical advice. A clinician’s test selection and interpretation, diagnosis, and patient management decisions should be based on his/her education, clinical expertise, and assessment of the patient.